Targeting the PEX Domain of MT1-MMP: Novel Cancer Therapy

靶向 MT1-MMP 的 PEX 结构域：新型癌症疗法

• 批准号: 7495931
• 负责人: Jian Cao
• 金额: $ 7.59万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7495931
• 关键词: 3-Dimensional; Adverse effects; Analytical Chemistry; Award; Base Sequence; Basement membrane; Behavior; Biological; Blood; Blood Vessels; CD44 Antigens; Cancer Model; Cancer Research Project; Carcinoma; Carcinoma in Situ; Catalytic Domain; Cell Adhesion Molecules; Cell Nucleus; Cell Proliferation; Cell Surface Proteins; Cell surface; Cell-Cell Adhesion; Cells; Cellular Morphology; Class; Cleaved cell; Collagen Type I; Complex; Computer Simulation; Data; Development; Diagnostic Neoplasm Staging; Dissection; Doctor of Medicine; E-Cadherin; Early treatment; Epithelial; Experimental Models; Extracellular Matrix; Extracellular Matrix Degradation; Figs - dietary; Fostering; Gel; Gene Expression Profile; Genetic Transcription; Goals; Grant; Growth; Hemopexin; In Situ; In Vitro; Interstitial Collagenase; Invasive; Lead; Loss of E-cadherin Expression; Lymph; Malignant Neoplasms; Malignant neoplasm of prostate; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mediating; Mesenchymal; Modeling; Mutagenesis; Neoplasm Metastasis; PHEX protein; Peptides; Pharmaceutical Preparations; Play; Process; Property; Prostatic Neoplasms; Protein Overexpression; Recombinant DNA; Recombinants; Research Personnel; Role; Safety; Signal Pathway; Specificity; Staging; Techniques; Tumor Cell Invasion; Tumor stage; base; cancer cell; cancer therapy; cell motility; chemokine; design; drug development; drug discovery; epithelial to mesenchymal transition; human MMP14 protein; in vivo; in vivo Model; inhibitor/antagonist; neoplastic cell; novel; prevent; proMMP-2; programs; three dimensional structure; tool; tumor progression

Epithelial-to-mesenchymal transition (EMT) has emerged as a critical step in the early stage of cancer. Better understanding of the mechanism of EMT will foster the development of inhibitors to prevent cancer progression. Considerable evidence has implicated membrane type 1-matrix metalloproteinase (MT1-MMP) in EMT and conversion to aggressive cancers. MT1-MMP activation of proMMP-2 and degradation of extracellular matrix (ECM) components are involved in cancer progression. MT1-MMP also cleaves numerous cell surface proteins, growth factors, and chemokines. We recently demonstrated that MT1-MMP: 1) cleaves E-cadherin at the cell-cell adherins junctions; 2) promotes cell migration/scattering in 3D type I collagen gels; 3) regulates cell proliferation in vitro and in vivo; and 5) changes cell morphology in 3D type I collagen gels. We also demonstrated that the hemopexin (PEX) domain of MT1-MMP plays a crucial role in cancer cell migration and pinpointed the regions required for MT1-MMP-mediated cell migration. Targeting the PEX domain with recombinant MT1-MMP PEX protein resulted in interference with MT1-MMP-induced cell migration. The primary goal of this grant is to define the involvement of the catalytic and non catalytic activities of MT1 -MMP in EMT. This characterizationwill facilitate our development of specific non-catalytic domain inhibitors of MT1-MMP that will be employed to interfere with cancer progression. To achieve this aim, the function of MT1-MMP in EMT in 3D cultured cancer cells will be examined. EMT-related transcription programs and signaling pathways will be evaluated. Based on a computational model of MT1-MMP and similarity with other MMPs, minimum motif(s) in the PEX domain of MT1-MMP required for cancer cell migration will be identified using a mutagenesis approach. Formation of homodimer and/or heterooligomer of MT1-MMP through PEX domain will be determined. Based on the identification of crucial PEX motifs, specific MT1-MMP inhibitory peptides will be designed and characterized using analytical chemistry and cell biological approaches. Functional inhibitory peptides will be produced and evaluated in an in vivo cancer model. The long-term goal is to develop a lead compound that will be modified to produce a MT1-MMP inhibitory drug with minimal side effects for treatment of cancer. I propose that the current project will help us to better understand cancer progression and lead to the development of novel basic tools for treatment of early stage cancer.

上皮-间质转化（EMT）已成为癌症早期阶段的关键步骤。更好 了解EMT的机制将促进抑制剂的发展，以防止癌症 进展大量的证据表明，膜型1-基质金属蛋白酶（MT 1-MMP）在 EMT和转化为侵袭性癌症。MT 1-MMP激活proMMP-2和降解 细胞外基质（ECM）成分参与癌症进展。MT 1-MMP还切割许多 细胞表面蛋白、生长因子和趋化因子。我们最近证明，MT 1-MMP：1）切割 E-钙粘蛋白在细胞-细胞粘附蛋白连接处; 2）促进细胞在3D I型胶原凝胶中的迁移/分散; 3)在体外和体内调节细胞增殖;和5）改变3D I型胶原凝胶中的细胞形态。我们 也证明了MT 1-MMP的血红素结合蛋白（PEX）结构域在癌细胞迁移中起着至关重要的作用 并精确定位了MT 1-MMP介导的细胞迁移所需的区域。靶向PEX结构域， 重组MT 1-MMPPEX蛋白干扰MT 1-MMP诱导的细胞迁移。的 这项资助的主要目标是确定MT 1-MMP的催化和非催化活性参与 急救员这一特性将有助于我们开发特异性的非催化结构域抑制剂， MT 1-MMP将用于干扰癌症进展。为了实现这一目标， 将检查3D培养的癌细胞中EMT中的MT 1-MMP。EMT相关转录程序和 将评估信号通路。基于MT 1-MMP的计算模型和与其他模型的相似性， 将鉴定MMP，即癌细胞迁移所需的MT 1-MMP的PEX结构域中的最小基序 使用诱变方法。通过PEX形成MT 1-MMP的同源二聚体和/或异源寡聚体 域将被确定。基于关键PEX基序的鉴定，特异性MT 1-MMP抑制剂 将使用分析化学和细胞生物学方法来设计和表征肽。 将在体内癌症模型中产生和评价功能性抑制肽。长期目标是 开发一种先导化合物，将其修饰以产生副作用最小的MT 1-MMP抑制药物 治疗癌症的效果。我建议目前的项目将有助于我们更好地了解癌症 进展，并导致用于治疗早期癌症的新的基本工具的发展。